Our approach toward the elucidation of mechanisms associated with initiation and promotion in human cancer has been to study in detail an inherited form of cancer, adenomatosis of the colon and rectum (ACR). In these studies we have proposed that skin fibroblasts (FS) derived from normal-appearing biopsies of gene-carriers exist in an initiated state due to a dominant mutation. The apparent susceptibility of ACR cells to further transformation by oncogenic viruses both SV40 and KiMSV and chemical and physical agents indicates that genetic information residing within these cells, probably in the form of a relatively limited and specific number of DNA sequences associated with the ACR mutation, renders them more sensitive to these three distinct classes of carcinogens. Our findings suggest a systemic disorder of stromal cells in ACR individuals that might provide insight about carcinogenic mechanisms involving the large bowel. Through the identification of transformation-related phenotypic expression in ACR cells, we are able to delineate precursor state-gene carriers of this form of cancer. These phenotypic abnormalities may also help to identify high risk groups most likely to benefit from screening programs.